6-Dehydrogingerdione, an active constituent of dietary ginger, induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human breast cancer cells.

This study is the first to investigate the anticancer effect of 6-dehydrogingerdione (DGE), an active constituent of dietary ginger, in human breast cancer MDA-MB-231 and MCF-7 cells. DGE exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclin B1, cyclin A, Cdc2 and Cdc25C. DGE also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. DGE triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activation. We also found the generation of reactive oxygen species is a critical mediator in DGE-induced cell growth inhibition. DGE clearly increased the activation of apoptosis signal-regulating kinase 1 and c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase 1/2 (ERK1/2) and p38. In addition, antioxidants vitamin C and catalase significantly decreased DGE-mediated JNK activation and apoptosis. Moreover, blocking JNK by specific inhibitors suppressed DGE-triggered mitochondrial apoptotic pathway. Taken together, these findings suggest that a critical role for reactive oxygen species and JNK in DGE-mediated apoptosis of human breast cancer.

[1]  A. A. Rahuman,et al.  Mosquito larvicidal activity of isolated compounds from the rhizome of Zingiber officinale , 2008, Phytotherapy research : PTR.

[2]  A. Pandiella,et al.  Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options , 2008, Clinical Cancer Research.

[3]  Y. Shukla,et al.  In vitro and in vivo modulation of testosterone mediated alterations in apoptosis related proteins by [6]-gingerol. , 2007, Molecular nutrition & food research.

[4]  P. Kuo,et al.  Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. , 2007, Cancer research.

[5]  Y. Shukla,et al.  Cancer preventive properties of ginger: a brief review. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[6]  S. Cory,et al.  The Bcl-2 apoptotic switch in cancer development and therapy , 2007, Oncogene.

[7]  Ray Liu,et al.  6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism. , 2007, Journal of agricultural and food chemistry.

[8]  Y. Kondo,et al.  Eupalmerin acetate, a novel anticancer agent from Caribbean gorgonian octocorals, induces apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway , 2007, Molecular Cancer Therapeutics.

[9]  Liying Wang,et al.  Reactive Oxygen Species Mediate Caspase Activation and Apoptosis Induced by Lipoic Acid in Human Lung Epithelial Cancer Cells through Bcl-2 Down-Regulation , 2006, Journal of Pharmacology and Experimental Therapeutics.

[10]  Young-Mi Ham,et al.  Ginsenoside-Rh2-Induced Mitochondrial Depolarization and Apoptosis Are Associated with Reactive Oxygen Species- and Ca2+-Mediated c-Jun NH2-Terminal Kinase 1 Activation in HeLa Cells , 2006, Journal of Pharmacology and Experimental Therapeutics.

[11]  H. Masutani,et al.  Redox regulation of human thioredoxin network. , 2006, Antioxidants & redox signaling.

[12]  P. Schumacker,et al.  Reactive oxygen species in cancer cells: live by the sword, die by the sword. , 2006, Cancer cell.

[13]  Y. Hsu,et al.  Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Induces Apoptosis and Cell Cycle Arrest in A549 Cells through p53 Accumulation via c-Jun NH2-Terminal Kinase-Mediated Phosphorylation at Serine 15 in Vitro and in Vivo , 2006, Journal of Pharmacology and Experimental Therapeutics.

[14]  Shivendra V. Singh,et al.  c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide–Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells , 2006 .

[15]  M. Valko,et al.  Free radicals, metals and antioxidants in oxidative stress-induced cancer. , 2006, Chemico-biological interactions.

[16]  Corinne E Griguer,et al.  Xanthine oxidase-dependent regulation of hypoxia-inducible factor in cancer cells. , 2006, Cancer research.

[17]  C. Hsieh,et al.  Thioredoxin‐ASK1 complex levels regulate ROS‐mediated p38 MAPK pathway activity in livers of aged and long‐lived Snell dwarf mice , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  Angel Ortega,et al.  Glutathione in Cancer Biology and Therapy , 2006, Critical reviews in clinical laboratory sciences.

[19]  L. Bundy,et al.  C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells , 2005, Molecular Cancer.

[20]  Seong-Jin Kim,et al.  Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. , 2005, Biochemical pharmacology.

[21]  S. Shyue,et al.  Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. , 2005, Biochemical pharmacology.

[22]  H. Abdel-Aziz,et al.  5-HT3 receptor blocking activity of arylalkanes isolated from the rhizome of Zingiber officinale. , 2005, Planta medica.

[23]  C. Teng,et al.  Isolation of a Natural Antioxidant, Dehydrozingerone from Zingiber officinale and Synthesis of Its Analogues for Recognition of Effective Antioxidant and Antityrosinase Agents , 2005, Archives of pharmacal research.

[24]  L. Hawthorn,et al.  Up-regulation of c-Jun-NH2-kinase pathway contributes to the induction of mitochondria-mediated apoptosis by alpha-tocopheryl succinate in human prostate cancer cells. , 2005, Molecular cancer therapeutics.

[25]  A. Murakami,et al.  Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes , 2004, FEBS letters.

[26]  A. Nebreda,et al.  Regulation of Cdc25C Activity During the Meiotic G2/M Transition , 2004, Cell cycle.

[27]  Xiaoling Jin,et al.  Diarylheptanoids from the rhizomes of Zingiber officinale. , 2004, Phytochemistry.

[28]  Fei Chen,et al.  Reactive Oxygen Species (ROS), Troublemakers between Nuclear Factor-κB (NF-κB) and c-Jun NH2-terminal Kinase (JNK) , 2004, Cancer Research.

[29]  H. Daniel,et al.  Ascorbic acid suppresses drug-induced apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. , 2003, Carcinogenesis.

[30]  Hsien-yu Wang,et al.  Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. , 2003, Cancer letters.

[31]  M. Hengartner.  The biochemistry of apoptosis , 2000, Nature.

[32]  Y. Surh,et al.  Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. , 1998, Cancer letters.

[33]  T. Hunter,et al.  The role of Cdc2 feedback loop control in the DNA damage checkpoint in mammalian cells. , 1997, Cancer research.

[34]  L. Loeb,et al.  Reactive oxygen species in tumorigenesis. , 1994, Cancer research.

[35]  W D Flanders,et al.  The lifetime risk of developing breast cancer. , 1993, Journal of the National Cancer Institute.

[36]  U. Sankawa,et al.  Inhibitors of prostaglandin biosynthesis from ginger. , 1982, Chemical & pharmaceutical bulletin.

[37]  V. Freedman,et al.  Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium. , 1974, Cell.

[38]  K. Miller,et al.  Development of new targeted therapies for breast cancer , 2008, Breast cancer.

[39]  F. Meyskens,et al.  UC Irvine UC Irvine Previously Published Works Title Reactive oxygen species : a breath of life or death ? , 2007 .